There are 22 million people worldwide with heart failure with a total cost this in the U.S. this year of 37 billion dollars. Yet, only two thousand Americans will receive heart transplants and even fewer will receive mechanical ventricular assist devices. Recently, it has been demonstrated that AAV9 encoding S100A1 reverses remodeling in a porcine model of ischemic heart failure with near complete molecular and functional rescue of the heart failure phenotype, the first-ever dramatic success of gene therapy for heart failure in a large animal model. Simultaneously, our collaborator, Dr. Roger Hajjar's pioneering work lead to the first-ever successful Phase IIA clinical trial of heart failure gene therapy (Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease), the CUPID trial, using AAV1 encoding SERCA2a as therapy for patients with advanced heart failure. However, both the SERCA2a (CUPID) clinical trial, and the preclinical studies using the S100A1 transgene, utilized inefficient (intracoronary delivery, CUPID trial), and regional rather than global vector delivery methods (pressurized coronary venous retroinfusion, S100A1 preclinical study), severely limiting their respective potential therapeutic impact in patients. In our prior funding period, we developed a novel vector- mediated cardiac gene delivery platform, Molecular Cardiac Surgery with Recirculating Delivery (MCARD) a safe, exciting new potentially minimally invasive cardiac surgical technique that uniquely allows for in situ, multiple-pass recirculation of recombinant vector in the isolated coronary circulation in large animals. MCARD leads to a >100 fold increase in the number of vector genomes delivered to the LV compared to existing gene delivery methods and is 10000 times more geographically specific to the heart. We plan to utilize MCARD, the most efficient and cardiac-specific gene delivery platform in the world to deliver the highly cardiotropic AAV serotypes scAAV6, scAAV9 and ssAAV9) encoding the two most promising transgenes (S100A1 and SERCA2a) in ovine ischemic heart failure models that closely mimic human ischemic cardiomyopathy. We use 3D MRI studies to assess load-independent and load- dependent indices of cardiac mechanics and myocardial energetics. The effects of gene expression on remodeling, calcium signaling, molecular heart failure markers and survival will be assessed for up to one year. This proposal will lead directly to promising new clinical trials for heart failure.